Alteration of functional connectivity in the cortex and major brain networks of non-human primates following focused ultrasound exposure in the dorsal striatum
Dong Liu, Fabian Munoz, Soroosh Sanatkhani, Antonios N. Pouliopoulos, Elisa E. Konofagou, Jack Grinband, Vincent P. Ferrera
Brain Stimulation 2023, 16, 1196-1204 · 10.1016/j.brs.2023.08.003
Abstract
Background Focused ultrasound (FUS) is a non-invasive neuromodulation technology that is being investigated for potential treatment of neurological and psychiatric disorders. FUS combined with microbubbles can temporarily open the intact blood-brain barrier (BBB) of animals and humans, and facilitate drug delivery. FUS exposure, either with or without microbubbles, has been demonstrated to alter the behavior of non-human primates (NHP), and previous studies have demonstrated the transient and long-term effects of FUS neuromodulation on functional connectivity using resting state functional MRI. The behavioral effects of FUS vary depending on whether or not it is applied in conjunction with microbubbles to open the BBB, but it is unknown whether opening the BBB affects functional connectivity differently than FUS alone. Objective To compare the effects of applying FUS alone (FUS neuromodulation) and FUS with microbubbles (FUS-BBB opening) on changes of resting state functional connectivity in NHP. Methods We applied 2 min FUS exposure without (neuromodulation) and with microbubbles (BBB opening) in the dorsal striatum of lightly anesthetized non-human primates, and acquired resting state functional MRI 40 min respectively after FUS exposure. The functional connectivity (FC) in the cortex and major brain networks between the two approaches were measured and compared. Results When applying FUS exposure to the caudate nucleus of NHP, we found that both FUS neuromodulation can activate FC between caudate and insular cortex, while inhibiting the FC between caudate and motor cortex. FUS-BBB opening can activate FC between the caudate and medial prefrontal cortex, and within the frontotemporal network (FTN). We also found both FUS and FUS-BBB opening can significantly activate FC within the default mode network (DMN). Conclusion The results suggest applying FUS to a deep brain structure can alter functional connectivity in the DMN and FTN, and that FUS neuromodulation and FUS-mediated BBB opening can have different effects on patterns of functional connectivity.
Abstract via europepmc.
Exposures
Exposure 1: FUS neuromodulation and FUS-mediated BBB opening (with microbubbles) of right caudate/dorsal striatum
Target: caudate nucleus — “right caudate nucleus (dorsal striatum)”
Device: Sonic Concepts · Sonic Concepts · H-107 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 10 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 2 | ✓✓✓ |
| Duty cycle (%) | 2pulse duration × PRF gives 2% | ✓✓✓ |
| Sonication duration (s) | 120 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | 800, 400swept | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Ispta, domain unspecified (W/cm²) | 0.157, 0.0392swept | ✓✓✓ |
FUS generated by the single element FUS transducer was applied on NHPs O and P (FUS-only neuromodulation group) for 2 min with derated PNP of 800 kPa, 2 Hz PRF, 10 ms pulse duration and 2% duty cycle. The same FUS parameters but with derated PNP of 400 kPa were applied on NHPs M and T (FUS-BBB opening group), combined with intravenous microbubbles injected 10 s after starting sonication. Resting-state fMRI was acquired starting approximately 45 min after the 2-min FUS exposure.
Flags from extraction
species— The paper refers only to 'NHPs' throughout and does not state the macaque species.n_subjects— Paper states group sizes (2 FUS-only, 2 FUS+MB) but never an explicit combined total of animals exposed to ultrasound; recorded as a list of group sizes per instructions.exposures[0].in_situ.pressure_kpa— The two pressures (800 kPa, 400 kPa) correspond respectively to the FUS-only neuromodulation group and the FUS+microbubbles BBB-opening group; both target the same site/frequency so are combined into one exposure with paired lists rather than treated as a dose change alone, since microbubble co-administration differs between the two.adverse_events— This study does not itself report on adverse events/safety monitoring outcomes for the animals; safety of the 400 kPa protocol is only referenced from prior publications.